关于蛋白质折叠的理论模型.pptVIP

* * * 脯氨酸残基紧紧地结合在结合沟的疏水口袋中，并且羧基端氧原子与蛋白质的的碱性侧链形成氢键，肽片段与疏水环境的结合，通过减少肽基团的电荷分离而促进了顺反异构化作用，并产生了具有单键特征的肽键，同时与Cyclophilin 的紧密疏水相互作用，可使肽基团的几何学上变形产生异构化作用这两种机理或它们的组合将减少绕肽键转动的能垒。此能量是顺反异构化所必需的 Prolyl peptide isomerases (PPIases) catalyze the rapid equilibration of cis–trans conformers of proline-containing peptide bonds. These backbone conformational changes play a pivotal role in protein folding. Moreover, the polypeptide backbone structural change centered around proline-containing peptide bonds can result in a kink in the polypeptide chain and, therefore, conformationally regulate a wide range of biological activities (2), including some activities resulting in disease. To date, three families of highly conserved PPIases have been identified, namely, cyclophilins (Cyp) , FK506 binding proteins (FKBPs) and parvulins . The Cyp and FKBP family members are also collectively termed immunophilins because of their role as binding partners for cyclosporine A and FK506, both of which serve as immunosuppressants. The most widely studied member of the parvulin family human Pin1, distinguishes itself from Cyp and FKBP through its unique substrate specificity for the phosphorylated Ser/Thr-Pro (P.Ser/P.Thr-Pro) motif Structural Basis for High-Affinity Peptide Inhibition of Human Pin1 the PPIase activity of Pin1 will greatly accelerate the reestablishment of the trans-to-cis equilibria of these dipeptide segments, ultimately affecting the underlying biological pathways By altering the cis–trans state of P.Ser/P.Thr-Pro peptide bonds, Pin1 catalyzes peptide backbone conformation changes that can then alter the catalytic activity, stability, subcellular localization, and the rate and extent of dephosphorylation of phospho-protein targets Pin1 can amplify oncogenic signals and is highly expressed in several human tumors. Loss of Pin1 function triggers apoptosis, suppresses, the transformed phenotype in some cell lines, and can even prevent oncogenic transformation. In contrast, Pin1 ove